粘附分子在造血细胞稳态调节和恶性转化中发挥着重要作用。白血病细胞粘附分子的异常表达加速疾病进展和药物耐药性的发展。因此，靶向粘附分子是一种吸引人的抗白血病治疗策略。本研究中，我们研究了细胞内酰胺激酶-1（CYTH1）在急性髓系白血病（AML）中的预后作用和功能意义。对来自GEPIA和BloodSpot数据库的AML患者数据进行分析发现，CYTH1在AML中显著过表达且与预后独立相关。使用AML细胞系和AML异种移植小鼠模型进行功能实验验证了CYTH1的减少明显抑制了白血病细胞的粘附，迁移，归巢和移植，在延缓疾病进展和延长动物存活时间方面发挥了作用。CYTH1抑制剂SecinH3通过破坏白血病粘附和存活程序，在体外和体内均具有抗白血病效果。与CYTH1敲减结果一致，SecinH3通过降低ITGB2表达抑制整合素相关的粘附信号传导。SecinH3处理有效诱导一系列具有混合谱系白血病基因重排的AML细胞系（MOLM-13，MV4-11和THP-1）的凋亡，并通过降低抗凋亡蛋白MCL1的表达部分抑制了其生长。此外，我们证明SecinH3与BCL2选择性抑制剂ABT-199（venetoclax）协同抑制ABT-199耐药白血病细胞的增殖并促进凋亡。综上所述，我们的结果不仅揭示了CYTH1在细胞粘附介导的白血病发生中的作用，还提出了一种新的AML组合治疗策略。© 2023作者，上海中科院上海药物研究所和中国药理学会独家许可。

Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.